Project Summary This application is a competing continuation of an Autism Center of Excellence (ACE) Network grant. The initial grant supported a prospective, longitudinal examination of brain and behavior at 6, 12 and 24 months in infants at high familial risk (HR) for autism. By the completion of this initial study 400 HR and 150 low risk infants will have entered this study. Results reveal that HR infants who go on to have autism at 24 months have impairments in visual orienting and motor behavior at 6 months of age, which may lay the foundation for the emergence of the defining features of autism (social deficits, repetitive behaviors) observed in these same infants by 12 months of age. Aberrant white matter tract development is detectable by 6 months of age in infants classified as autistic at 24 months (1), with further widespread abnormalities in white matter tract development and an increased rate of brain volume growth observed over the 6-24 month period. Thus, our research establishes, for the first time, that such brain changes occur concurrently with the emergence of behavioral abnormalities in ASD. Taken together, these findings point to brain and behavior changes during the 1st year (and as early as 6 months of age) as being critically important in the onset and development of autistic behavior. In this application we propose to follow up these findings by conducting earlier (3 months), more frequent (3, 6, 9, 12, 15, 24 months) and more in depth examination of the trajectories of brain and behavior development in 200 HR and 60 LR infants, to more fully understand brain-behavior relationships during this critically important period preceding and coinciding with the emergence of the defining features of autism. We also propose to conduct follow up behavioral/diagnostic evaluations of our original sample of 400 HR subjects at 36 to 60 months of age, a time when the diagnosis of autism is considered to be more stable. This will allow us to map the trajectories of brain and behavior development and test the association between clinical ASD diagnosis and variation in developmental trajectories. Finally we propose to conduct an analysis of child and family level characteristics relevant to elucidating an early prediction model of later autism in the joint cohort of 600 HR subjects. The delineation of brain and behavior trajectories in early development and the ability to predict autism diagnosis from preclinical risk markers during infancy, prior to clinical diagnosis and during a period of substantial post-natal brain plasticity, when children may benefit maximally from early detection and intervention, has the potential to significantly improve the lives of affected individuals.